Directed screening of compounds selected from the Glaxo registry file for contractile activity on the isolated guinea pig gallbladder (GPGB) identified a series of 1,5-benzodiazepines with peripheral cholecystokinin (CCK) receptor agonist activity. Agonist efficacy within this series was modulated by variation of substituents on the N1-anilinoacetamide moiety. Remarkably, a single methyl group confers agonist activity, with an N-isopropyl substituent providing optimal efficacy. Hydrophilic substituents on the anilino nitrogen abolish agonist activity or produce antagonists of CCK. In contrast, hydrophilic electron-donating groups at the para-position of the anilino ring enhance or maintain in vitro and in vivo agonist activity. Despite decreased affinity for the human CCK-A receptor, relative to CCK-8, some of these compounds are equipotent to CCK as anorectic agents in rats following intraperitoneal administration.

This study examines immunoreactive levels of oxytocin (OT) and arginine-vasopressin (AVP) from acid extracts of the paraventricular nucleus (PVN), supraoptic nucleus (SON), anterior commissural nucleus (ACN) and the suprachiasmatic nucleus (SCN) as well as selected extrahypothalamic sites in pregnant or postpartum (PP) rats. Animals are sacrificed between 08.30 and 10.30 h 16 or 22 days after sperm is detected in their vaginal smears or on the morning after parturition. Peptide levels of pregnant or PP animals are compared to levels of ovariectomized (OVXed) rats sacrificed and assayed simultaneously. OT immunoreactive levels in the PVN and SON are significantly elevated in late pregnancy and PP. OT content of the ACN is elevated on day 16, but drops to control levels by day 22 of pregnancy and day 1 PP. Concomitant with the falling OT content in the ACN at the end of pregnancy, samples from the ventral septum have significantly increased OT content on day 1 PP. In extracts including the nucleus of the tractus solitarius (NTS) and dorsal motor nucleus of the vagus (dMX) OT is also elevated on the day after parturition. AVP levels peak on the day before parturition in all hypothalamic nuclei examined. These increases are significantly greater than in OVXed controls in the PVN and SON. AVP levels in the lateral habenula are elevated both on day 16 of pregnancy and on the first day PP. From these data we conclude that nonapeptide levels are altered across late pregnancy and early postpartum in some hypothalamic synthesis sites and in certain limbic and brainstem sites. We also postulate that OT is transported out of the ACN to extrahypothalamic sites around the time of parturition.

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We previously described a series of 3-(1H-indazol-3-ylmethyl)-1,5-benzodiazepine CCK-A agonists exemplified by compound 1 (GW 5823), which is the first reported binding selective CCK-A full agonist demonstrating oral efficacy in a rat feeding model. In this report we describe analogs of compound 1 designed to explore changes to the C3 and N1 pharmacophores and their effect on agonist activity and receptor selectivity. Agonist efficacy in this series was affected by stereoelectronic factors within the C3 moiety. Binding affinity for the CCK-A vs CCK-B receptor showed little dependence on the structure of the C3 moiety but was affected by the nature of the second substituent at C3. Structure-activity relationships at the N1-anilidoacetamide "trigger" moiety within the C3 indazole series were also investigated. Both agonist efficacy and binding affinity within this series were modulated by variation of substituents on the N1-anilidoacetamide moiety. Evaluation of several analogs in an vivo mouse gallbladder emptying assay revealed compound 1 to be the most potent and efficacious of all the analogs tested. The pharmacokinetic and pharmacodynamic profile of 1 in rats is also discussed.